While the oral mucosa effectively excludes HIV infection, it is host to a select group of opportunistic infections (OIs), which, for reasons not understood, are manifest in HIV infection and are sentinel of the progression to AIDS and failure of immune reconstitution therapy. As our unifying focus, we will explore the factors that contribute to innate immunity in the oral cavity. In this Program Project Application entitled: The Oral Mucosa in HIV Disease: innate Immunity, we propose four highly-integrated, multidisciplinary projects which are supported by two cores: Core A: the Administrative and Technical Support Core and Core B: the Clinical Core. As our unifying focus, we will explore the factors that contribute to innate immunity in the oral cavity. By design, the experiments proposed in the four projects range from broad-based approaches which aim to discover and characterize components of oral secretions which function in innate immunity to viral and microbial pathogens (Project 1: The Impact of HIV Disease on the Salivary Proteome), to the description and molecular characterization of the mechanism of action of specific anti-viral/microbial peptides (Project 2: Oral S100A8 and S100A9 in HIV Infection and Project 3: HIV-induced Alterations of Innate Oral Immune Defenses), to the characterization of HIV-induced alterations in the type I interferon system (Project 3). Information gained by these projects on the elements of the host response to HIV/HAART are complemented by direct characterization of the effect of these host molecules on the pathogens themselves, HIV, HPV and Candida albicans (C. albicans) (Project 1, 2, 3, and Project 4: Molecular Characterization of Candida-Host Interactions). Finally the direct effect of C. albicans on oral epithelial cells will be evaluated with the objective of learning how co-infection with OIs affect oral mucosal function in HIV disease (Project 4). As mandated by the RFA, and as has been our approach historically, we will bring the full force of cutting edge technologies such as mass spectrometry, genomics and DNA microarray analysis, Real Time RT-PCR and laser dissection microscopy (LDM) to bear on the study of the oral mucosa in HIV disease. Taking a concerted approach, the overarching goal of our program project will be to identify and characterize the range of innate immune factors expressed in the oral cavity and by so doing learn how these singly and together contribute to the underlying resistance of the oral mucosa to HIV infection and OIs which, in the oral cavity, are primary and immediate manifestations of immune failure. [unreadable] [unreadable]